PROJECT SUMMARY/ABSTRACT This proposal details a 4-year research plan designed to provide Dr. Danielle Ahn the foundation for future research endeavors as an independent physician-investigator researcher. To achieve this goal, this application describes a program to: 1) conduct a novel basic science research project under the mentorship of an interdisciplinary team of expert researchers led by Dr. Alice Prince, a leader in the host-pathogen interaction, innate immunity and infectious diseases; 2) continue to develop expertise in molecular biology, immunology and microbiology through hands-on experience, didactic interactions with mentors and graduate level coursework; 3) build a network of collaborators within Columbia University and elsewhere via research and participation at national meetings; and 4) prepare and submit an independent federal research grant with a translational focus. With a background in the practice of pediatric critical care medicine and the study of host- pathogen interactions, the candidate is poised to elucidate host-adapted mechanisms of impaired bacterial clearance. Specifically, her studies focus on infection with carbapenem-resistant Klebsiella pneumoniae (CRKP), a major cause of illness for patients in critical care units around the world. Preliminary data highlight the major knowledge gap regarding the host response to infection with CRKP because nearly all studies use a phenotypically different, laboratory reference strain K. pneumoniae ATCC 43816 (KPPR1). Comprehensive analysis of infection with a clinical isolate of CRKP showed the major influence of immunosuppressive monocytes, or monocytic-myeloid derived suppressor cells (M-MDSCs), recruited in response to infection with a CRKP isolate. This project is designed to understand how these highly influential cells impair bacterial clearance through multiple mechanisms. The candidate will accomplish this with 1) a murine model of pneumonia, 2) in vitro functional assays, 3) flow cytometry and 4) bacterial mutagenesis. The overall objective of this study is to understand how this organism has evolved to evade host mechanisms of bacterial clearance. Long-term, this will help identify novel therapies to treat severe pneumonia due to this opportunistic pathogen.